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Jay Jagannathan, John A. Butman, Russell R. Lonser, Alexander O. Vortmeyer, Christopher K. Zalewski, Carmen Brewer, Edward H. Oldfield and H. Jeffrey Kim

✓ Endolymphatic sac tumors (ELSTs) are locally invasive neoplasms that arise in the posterior petrous bone and are associated with von Hippel–Lindau (VHL) disease. These tumors cause symptoms even when microscopic in size (below the threshold for detectability on imaging studies) and can lead to symptoms such as hearing loss, tinnitus, vertigo, and facial nerve dysfunction. While the mechanisms of audiovestibular dysfunction in patients harboring ELSTs are incompletely understood, they have critical implications for management. The authors present the case of a 33-year-old man with VHL disease and a 10-year history of progressive tinnitus, vertigo, and left-sided hearing loss. Serial T1-weighted magnetic resonance (MR) imaging and computed tomography scans revealed no evidence of tumor, but fluid attenuated inversion recovery (FLAIR) MR imaging sequences obtained after hearing loss demonstrated evidence of left intralabyrinthine hemorrhage. On the basis of progressive disabling audiovestibular dysfunction (tinnitus and vertigo), FLAIR imaging findings, and VHL disease status, the patient underwent surgical exploration of the posterior petrous region, and a small (2-mm) ELST was identified and completely resected. Postoperatively, the patient had improvement of the tinnitus and vertigo. Intralabyrinthine hemorrhage may be an early and the only neuroimaging sign of an ELST in patients with VHL disease and audiovestibular dysfunction. These findings support tumor-associated hemorrhage as a mechanism underlying the audiovestibular dysfunction associated with ELSTs.

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Jay Jagannathan, Jason P. Sheehan and John A. Jane Jr.

✓ The treatment of patients with Cushing disease and without magnetic resonance (MR) imaging evidence of Cushing disease (that is, negative MR imaging) is discussed in this paper. Magnetic resonance imaging is the diagnostic modality of choice in Cushing disease, but in up to 40% of these patients negative imaging can be caused by tumor-related factors and limitations in imaging techniques. In cases in which the MR imaging is negative, it is critical to make sure that the diagnosis of Cushing disease is correct. This can be accomplished by performing a complete laboratory and imaging workup, including dexamethasone suppression tests, imaging of the adrenal glands, and inferior petrosal sinus sampling when appropriate. If these evaluations suggest a pituitary source of the hypercortisolemia, then transsphenoidal surgery remains the treatment of choice. The authors favor the endoscopic approach because it gives a wider and more magnified view of the sella and allows inspection of the medial cavernous sinus walls. Radiosurgery is an effective treatment option in patients with persistent Cushing disease. When a target cannot be found on MR imaging, one can target the entire sellar region with radiosurgery.

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Charles A. Sansur, Kai-Ming G. Fu, Rod J. Oskouian Jr., Jay Jagannathan, Charles Kuntz iv and Christopher I. Shaffrey

✓ Ankylosing spondylitis (AS) is an inflammatory rheumatic disease whose primary effect is on the axial skeleton, causing sagittal-plane deformity at both the thoracolumbar and cervicothoracic junctions. In the present review article the authors discuss current concepts in the preoperative planning of patients with AS. The authors also review current techniques used to treat sagittal-plane deformity, focusing on pedicle subtraction osteotomy at the thoracolumbar junction, as well as cervical extension osteotomy at the cervicothoracic junction.

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Jay Jagannathan, Russell R. Lonser, Rene Smith, Hetty L. DeVroom and Edward H. Oldfield

Object

Despite the frequency of cerebellar hemangioblastomas in von Hippel–Lindau (VHL) disease, their optimum contemporary management has not been defined, and is made complex because of the multiple, progressive, and protean nature of the tumors found in patients with this disorder. To examine modern management and outcomes of cerebellar hemangioblastomas in VHL disease, the authors reviewed findings in patients with this disease who underwent resection of cerebellar hemangioblastomas.

Methods

Consecutive patients with VHL disease who underwent surgery for cerebellar hemangioblastoma(s) at the National Institutes of Health were included. Eighty consecutive patients (44 female and 36 male patients) underwent 126 operations for removal of 164 cerebellar hemangioblastomas (age at surgery 37.8 ± 10.3 years, follow-up duration 96.0 ± 60.3 months). Serial clinical examinations, imaging studies, and operative records were analyzed.

Results

Symptoms and signs included headache (94 operations; 75%), ataxia (55%), dysmetria (29%), and hydrocephalus (28%). Although the primary objective of surgery was resection of the hemangioblastoma considered responsible for symptoms (136 of the hemangioblastomas [83%]), 28 additional hemangioblastomas (17%) were removed during the same surgeries. Tumors associated with symptoms were larger (diameter 1.8 ± 1.9 cm; volume 2.8 ± 3.4 cm3; p < 0.05) and more likely to be associated with peritumoral edema or peritumoral cysts (100% associated with edema and/or cyst; p < 0.05) than asymptomatic tumors (diameter 1.1 ± 0.9 cm; volume 0.7 ± 0.4 cm3; 18%). More tumors were located in the posterior (74%) compared with the anterior (26%) half of the cerebellum (p < 0.05). Three months after resection, symptom improvement/stabilization had occurred following 124 of the operations (98%). Preoperative hydrocephalus resolved after tumor removal in 33 cases (94%) and did not require cerebrospinal fluid diversion. Long-term imaging follow-up (61.5 ± 15.0 months) revealed no recurrences.

Conclusions

Symptoms and signs caused by cerebellar hemangioblastomas in VHL disease are associated with edema and peritumoral cyst formation/propagation and are treated safely and effectively with resection. Cerebrospinal fluid diversion is rarely necessary after complete tumor removal in patients with preoperative hydrocephalus. Cerebellar hemangioblastomas are preferentially distributed in the posterior half of the cerebellum, as they are in the brainstem and spinal cord. Tumor recurrence is avoided by meticulous extracapsular resection.

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Jay Jagannathan, Christopher I. Shaffrey, Rod J. Oskouian, Aaron S. Dumont, Christian Herrold, Charles A. Sansur and John A. Jane Sr.

Object

Although the clinical outcomes following anterior cervical discectomy and fusion (ACDF) surgery are generally good, 2 major complications are graft migration and nonunion. These complications have led some to advocate rigid internal fixation and/or cervical immobilization postoperatively. This paper examines a single-surgeon experience with single-level ACDF without use of plates or hard collars in patients with degenerative spondylosis in whom allograft was used as the fusion material.

Methods

The authors conducted a retrospective review of a prospective database of (Cloward-type) ACDF operations performed by the senior author (J.A.J.) between July 1996 and June 2005. Radiographic follow-up included static and flexion/extension radiographs obtained to assess fusion, focal and segmental kyphosis, and change in disc space height. At most recent follow-up, the patients' condition was evaluated by an independent physician examiner. The Odom criteria and Neck Disability Index (NDI) were used to assess outcome.

Results

One hundred seventy patients underwent single-level ACDF for degenerative pathology during the study period. Their most common presenting symptoms were pain, weakness, and radiculopathy; 88% of patients noted ≥ 2 neurological complaints. The mean hospital stay was 1.76 days (range 0–36 days), and 3 patients (2%) had major immediate postoperative complications requiring reoperation. The mean duration of follow-up was 22 months (range 12–124 months). Radiographic evidence of fusion was present in 160 patients (94%). Seven patients (4%) showed radiographic evidence of pseudarthrosis, and graft migration was seen in 3 patients (2%). All patients had increases in focal kyphosis at the operated level on postoperative radiographs (mean −7.4°), although segmental alignment was preserved in 133 patients (78%). Mean change in disc space height was 36.5% (range 28–53%). At most recent clinical follow-up, 122 patients (72%) had no complaints referable to cervical disease and were able to carry out their activities of daily living without impairment. The mean postoperative NDI score was 3.2 (median 3, range 0–31).

Conclusions

Single-level ACDF without intraoperative plate placement or the use of a postoperative collar is an effective treatment for cervical spondylosis. Although there is evidence of focal kyphosis and loss of disc space height, radiographic evidence of fusion is comparable to that attained with plate fixation, and the rate of clinical improvement is high.

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Jason P. Sheehan and Jay Jagannathan

Intracranial radiosurgery has been proved effective for the treatment of brain metastasis. The treatment of paraspinal and spinal metastasis with spinal radiosurgery represents a natural extension of the principles of intracranial radiosurgery. However, spinal radiosurgery is a far more complicated process than intracranial radiosurgery. Larger treatment volumes, numerous organs at risk, and the inability to utilize rigid, frame-based immobilization all contribute to the substantially more complex process of spinal radiosurgery.

Beyond the convenience of a shorter duration of treatment for the patient, spinal radiosurgery affords a greater biological equivalent dose to a metastatic lesion than conventional radiotherapy fractionation schemes. This appears to translate into a high rate of tumor control and fast pain relief for patients. The minimally invasive nature of this approach is consistent with trends in open spinal surgery and helps to maintain or improve a patient's quality of life. Spinal radiosurgery has expanded the neurosurgical treatment armamentarium for patients with spinal and paraspinal metastasis.

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Jay Jagannathan, Stuart Walbridge, John A. Butman, Edward H. Oldfield and Russell R. Lonser

Object

Convection-enhanced delivery (CED) is increasingly used to investigate new treatments for central nervous system disorders. Although the properties of CED are well established in normal gray and white matter central nervous system structures, the effects on drug distribution imposed by ependymal and pial surfaces are not precisely defined. To determine the effect of these anatomical boundaries on CED, the authors infused low MW and high MW tracers for MR imaging near ependymal (periventricular) and pial (pericisternal) surfaces.

Methods

Five primates underwent CED of Gd-diethylenetriamine pentaacetic acid (Gd-DTPA; MW 590 D) or Gd-bound albumin (Gd-albumin; MW 72,000 D) during serial real-time MR imaging (FLAIR and T1-weighted sequences). Periventricular (caudate) infusions were performed unilaterally in 1 animal (volume of infusion [Vi] 57 μl) and bilaterally in 1 animal with Gd-DTPA (Vi = 40 μl on each side), and bilaterally in 1 animal with Gd-albumin (Vi = 80 μl on each side). Pericisternal infusions were performed in 2 animals with Gd-DTPA (Vi = 190 μl) or with Gd-albumin (Vi = 185 μl) (1 animal each). Clinical effects, MR imaging, and histology were analyzed.

Results

Large regions of the brain and brainstem were perfused with both tracers. Intraparenchymal distribution was successfully tracked in real time by using T1-weighted MR imaging. During infusion, the volume of distribution (Vd) increased linearly (R2 = 0.98) with periventricular (mean Vd/Vi ratio ± standard deviation; 4.5 ± 0.5) and pericisternal (5.2 ± 0.3) Vi, but did so only until the leading edge of distribution reached the ependymal or pial surfaces, respectively. After the infusate reached either surface, the Vd/Vi decreased significantly (ependyma 2.9 ± 0.8, pia mater 3.6 ± 1.0; p < 0.05) and infusate entry into the ventricular or cisternal cerebrospinal fluid (CSF) was identified on FLAIR but not on T1-weighted MR images.

Conclusions

Ependymal and pial boundaries are permeable to small and large molecules delivered interstitially by convection. Once infusate reaches these surfaces, a portion enters the adjacent ventricular or cisternal CSF and the tissue Vd/Vi ratio decreases. Although T1-weighted MR imaging is best for tracking intraparenchymal infusate distribution, FLAIR MR imaging is the most sensitive and accurate for detecting entry of Gd-labeled imaging compounds into CSF during CED.

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Jie Li, Hiroaki Okamoto, Chunyue Yin, Jay Jagannathan, Jun Takizawa, Sadao Aoki, Sven Gläsker, Elisabeth J. Rushing, Alexander O. Vortmeyer, Edward H. Oldfield, Ryuya Yamanaka and Zhengping Zhuang

Object

The lack of primary lymphoid tissue within the central nervous system (CNS) confounds our understanding of the pathogenesis of primary CNS lymphomas (PCNSLs). Comparing the protein expression of PCNSLs and sporadic systemic lymphomas (SSLs) provides a useful strategy for identifying a molecular signature that characterizes disease-associated features and provides information regarding tumor initiation and progression.

Methods

Seven diffuse large B-cell PCNSLs were selected to undergo 2D gel electrophoresis, and profiled proteomes from these PCNSLs were compared with those from 7 diffuse large B-cell SSLs. Distinguishing proteins were sequenced using mass spectrometry.

Results

Two-dimensional gel electrophoresis identified an average of 706 proteins from each specimen. Computerized gel analysis and manual reconfirmation revealed a 96% similarity in the proteomes of PCNSLs and SSLs. Comparative analysis identified 9 proteins significantly overexpressed (p < 0.05) and 16 proteins downregulated in PCNSLs. The proteomic findings were further validated using Western blot and immunohistochemical staining.

Conclusions

The similarities in proteomic patterns between PCNSLs and SSLs suggest that these tumor types share structural similarities, acquired during differentiation. The ultimate fate of lymphomatous cells (CNS vs systemic) may be related to differentially expressed proteins, which function in homing and host processing. Elucidating the roles of these differentially expressed proteins will prove valuable in understanding the pathogenesis of PCNSL.

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Jay Jagannathan, David O. Okonkwo, Hian Kwang Yeoh, Aaron S. Dumont, Dwight Saulle, Julie Haizlip, Jeffrey T. Barth, John A. Jane Sr. and John A. Jane Jr.

Object

The management strategies and outcomes in pediatric patients with elevated intracranial pressure (ICP) following severe traumatic brain injury (TBI) are examined in this study.

Methods

This study was a retrospective review of a prospectively acquired pediatric trauma database. More than 750 pediatric patients with brain injury were seen over a 10-year period. Records were retrospectively reviewed to determine interventions for correcting ICP, and surviving patients were contacted prospectively to determine functional status and quality of life. Only patients with 2 years of follow-up were included in the study.

Results

Ninety-six pediatric patients (age range 3–18 years) were identified with a Glasgow Coma Scale score < 8 and elevated ICP > 20 mm Hg on presentation. The mean injury severity score was 65 (range 30–100). All patients were treated using a standardized head injury protocol. The mean time course until peak ICP was 69 hours postinjury (range 2–196 hours). Intracranial pressure control was achieved in 82 patients (85%). Methods employed to achieve ICP control included maximal medical therapy (sedation, hyperosmolar therapy, and paralysis) in 34 patients (35%), ventriculostomy in 23 patients (24%), and surgery in 39 patients (41%). Fourteen patients (15%) had refractory ICP despite all interventions, and all of these patients died. Seventy-two patients (75%) were discharged from the hospital, whereas 24 (25%) died during hospitalization. Univariate and multivariate analysis revealed that the presence of vascular injury, refractory ICP, and cisternal effacement at presentation had the highest correlation with subsequent death (p < 0.05). Mean follow-up was 53 months (range 11–126 months). Three patients died during the follow-up period (2 due to infections and 1 committed suicide). The mean 2-year Glasgow Outcome Scale score was 4 (median 4, range 1–5). The mean patient competency rating at follow-up was 4.13 out of 5 (median 4.5, range 1–4.8). Univariate analysis revealed that the extent of intracranial and systemic injuries had the highest correlation with long-term quality of life (p < 0.05).

Conclusions

Controlling elevated ICP is an important factor in patient survival following severe pediatric TBI. The modality used for ICP control appears to be less important. Long-term follow-up is essential to determine neurocognitive sequelae associated with TBI.

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Pavan Jagannathan and Jay Jagannathan